Abstract 238: Critical Role of Ryanodine Receptor Bound Calmodulin to Prevent Catecholaminergic Polymorphic Ventricular Tachycardia
| Autor: | Masafumi Yano, Hitoshi Uchinoumi, Tetsuro Oda, Xiaojuan Xu, Go Fukui, Shinichi Okuda, Shigehiko Nishimura, Shigeki Kobayashi, Yoriomi Hamada, Takeshi Yamamoto, Masaki Tamitani, Yoshihide Nakamura, Takayoshi Kato |
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| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Calmodulin biology Physiology Ryanodine receptor Point mutation chemistry.chemical_element Calcium musculoskeletal system Ventricular tachycardia medicine.disease Catecholaminergic polymorphic ventricular tachycardia Ryanodine receptor 2 Endocrinology chemistry Internal medicine cardiovascular system medicine biology.protein Cardiology and Cardiovascular Medicine tissues |
| Zdroj: | Circulation Research. 125 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.125.suppl_1.238 |
| Popis: | Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using knock-in mouse (KI) model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitizes the channel to agonists, primarily mediated by defective inter-domain interaction within the RyR2 molecule and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there is a possible amino-acid substitution at the CaM-binding domain in the RyR2 (3584-3603) that can enhancethe binding affinity of CaM, and found that V3599K substitution showed the highest binding affinity of CaM to CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K/+) with a single amino acid substitution in the CaM-binding domain of the RyR2, and crossbred it with the heterozygous CPVT -associated R2474S/+ KI mouse to obtain a double heterozygous R2474S/V3599K KI mouse. The CPVT phenotypes—bidirectional or polymorphic ventricular tachycardia, spontaneous Ca2+ transients, and Ca2+ sparks—were all inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis. |
| Databáze: | OpenAIRE |
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